Monocyte chemotactic protein-2 activates CCR5 and blocks CD4/CCR5-mediated HIV-1 entry/replication.
Human immunodeficiency virus, type I (HIV-1) cell-type tropism is dictated by chemokine receptor usage: T-cell line tropic viruses use CXCR4, whereas monocyte tropic viruses primarily use CCR5 as fusion coreceptors. CC chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES (regulated on activation normal T cell expressed and secreted) inhibit CD4/CCR5-mediated HIV-1 cell fusion. MCP-2 is also a member of the CC chemokine subfamily and has the capacity to interact with at least two receptors including CCR-1 and CCR2B. In an effort to further characterize the binding properties of MCP-2 on leukocytes, we observed that MCP-2, but not MCP-1, effectively competed with MIP-1beta for binding to monocytes, suggesting that MCP-2 may interact with CCR5. As predicted, MCP-2 competitively inhibited MIP-1beta binding to HEK293 cells stably transfected with CCR5 (CCR5/293 cells). MCP-2 also bound to and induced chemotaxis of CCR5/293 cells with a potency comparable with that of MIP-1beta. Confocal microscopy indicates that MCP-2 caused remarkable and dose-dependent internalization of CCR5 in CCR5/293 cells. Furthermore, MCP-2 inhibited the entry/replication of HIV-1ADA in CCR5/293 cells coexpressing CD4. These results indicated that MCP-2 uses CCR5 as one of its functional receptors and is an additional potent natural inhibitor of HIV-1.
Gong
W
W
Intramural Research Support Program, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland 21702, USA.
Howard
O M
OM
Turpin
J A
JA
Grimm
M C
MC
Ueda
H
H
Gray
P W
PW
Raport
C J
CJ
Oppenheim
J J
JJ
Wang
J M
JM
D015704:CD4 Antigens / Q000502:physiology*; D002459:Cell Fusion / Q000502:physiology*; D002478:Cells, Cultured; D054412:Chemokine CCL8; D004705:Endocytosis; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D018945:Monocyte Chemoattractant Proteins / Q000378:metabolism*; D019713:Receptors, CCR5 / Q000378:metabolism / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D014779:Virus Replication / Q000502:physiology*
C515453:CCL8 protein, human; D015704:CD4 Antigens; D054412:Chemokine CCL8; D018945:Monocyte Chemoattractant Proteins; D019713:Receptors, CCR5; D011994:Recombinant Proteins